By University of North Carolina School of Medicine, [RxPG] The use of growth hormone therapy has been linked in some people to the development of colon polyps, a possible precursor to colorectal cancer  but medical researchers have debated the extent of a cancer risk.

In addition, the reason for a polyp link to growth hormone has been unclear. But new research from the University of North Carolina at Chapel Hill indicates the probable answer: loss of function of one of a pair of genes that normally would inhibit growth hormone signals inside the cell.

The study also offers a possible molecular marker that could help determine which people taking growth hormone therapy are at increased risk for colon polyps. Researchers already know that colon polyps tend to occur in people who already have excessive amounts of growth hormone, such as those with a disease called acromegaly, or gigantism.

Study senior author Dr. P. Kay Lund, professor of cell and molecular physiology within UNC's School of Medicine and a member of the UNC Lineberger Comprehensive Cancer Center, said she and her team had been interested in looking at the effect of a newly discovered inhibitor of cellular growth hormone signaling, suppressor of cytokine signaling-2, or SOCS2.

This molecule limits growth hormone action on the body and organ growth, but its role in growth hormone action on intestine is unknown, Lund said.

"Much of the work on SOCS2 had been done in cell cultures. We wanted to study it in vivo, in laboratory animals, with a focus on how it stops the action of cellular growth hormone."

The researchers thought an ideal way to study this issue would be to use an animal model of acromegaly, laboratory mice having excessive amounts of growth hormone.

The animals were crossed with animals in which the SOCS2 gene was deleted. The breeding generated animals with excessive growth hormone and one or two functional SOCS2 genes, but none with excessive growth hormone and no SOCS2 genes, an unexpected result.

But there was another surprise: While colon polyps did not develop in animals with excessive growth hormone and two functional SOCS genes, multiple polyps did develop in animals with excessive growth hormone and only one functioning SOCS2 gene.

"We discovered that losing this one copy of SOCS2, this 'haplotype insufficiency,' is enough to cause spontaneous polyp formation in these animals," Lund said, adding that the findings may have implications for humans.

"Haplotype insufficiency animal models are much closer to the normal human variation. Animals expressing just 50 percent normal levels of a protein can be thought of as reflecting the physiological variation that occurs in the general population."

According to Lund, expression levels of SOCS2 measured in, say, 100 people would almost certainly vary by at least 50 percent.

"So this really raises the issue that in a situation of growth hormone excess, such as acromegaly or, possibly, growth hormone therapy, SOCS2 may really be fundamental to dictating your risk of getting abnormalities in the colon."

On the other hand, Lund's research may apply to the variations found in response to growth hormone therapy for the gastrointestinal tract. This would include people with short-bowel syndrome, a group of problems affecting individuals who have had half or more of their small intestine surgically removed. Many people with short bowel syndrome are malnourished because their remaining small intestine is unable to absorb enough water, vitamins and other nutrients from food.

"What has been a puzzle there is that the response to growth hormone in these patients is very variable. Some seem to respond well and get a great benefit from this therapy, and some people don't respond well," Lund said.

"And we found that animals having 50 percent of normal expression levels of SOCS2 show much greater small intestinal growth to growth hormone therapy. So if low SOCS2 enhances the response of the small intestine to growth hormone, it says that patients that have lower SOCS2 may be the ones who favorably respond to this therapy."

Thus, depending on the clinical situation, levels of SOCS2 would either predict who might be at greater risk for colon polyps in the presence of an excess of growth hormone and who might best respond to growth hormone therapy for gastrointestinal conditions such as short bowel syndrome.

"Our future research with SOCS2 will be aimed at studies on human tissue samples to test variations in levels of SOCS2 in the intestine to predict risk of colonic polyps or the response of short bowel syndrome patients to therapeutic growth hormone. Future animal studies will test the role of SOCS2 in cancer models," Lund said.

Publication:
A report of the study appears in the April issue of the medical journal Endocrinology.
On the web:www.med.unc.edu

UNC co-authors with Lund were lead author Dr. Carmen Michaylira, a former graduate student in Lund's lab and now at the University of Pennsylvania; Nicole Ramocki, graduate student; Dr. James Simmons, research associate in cell and molecular physiology; C. Kirby Tanner, first-year medical student; Kirk McNaughton, research analyst in cell and molecular physiology; and Dr. John Woosley, asssociate professor of pathology and laboratory medicine. Co-author Dr. Christopher Greenhalgh from the Walter and Eliza Hall Institute in Melbourne, Australia, was an essential collaborator on the SOCS2 work.

Funding for the research came from the National Institute of Diabetes and Digestive and Kidney Diseases, a component of the National Institutes of Health.

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